Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.
Plasma liver-enzyme tests are widely used in the clinic for the diagnosis of liver diseases and for monitoring the response to drug treatment. There is considerable evidence that human genetic variation influences plasma levels of liver enzymes. However, such genetic variation has not been systematically assessed. In the present study, we performed a genome-wide association study of plasma liver-enzyme levels in three populations (total n = 7715) with replication in three additional cohorts (total n = 4704). We identified two loci influencing plasma levels of alanine-aminotransferase (ALT) (CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chromosome 22), one locus influencing gamma-glutamyl transferase (GGT) levels (HNF1A on chromosome 12), and three loci for alkaline phosphatase (ALP) levels (ALPL on chromosome 1, GPLD1 on chromosome 6, and JMJD1C-REEP3 on chromosome 10). In addition, we confirmed the associations between the GGT1 locus and GGT levels and between the ABO locus and ALP levels. None of the ALP-associated SNPs were associated with other liver tests, suggesting intestine and/or bone specificity. The mechanisms underlying the associations may involve cis- or trans-transcriptional effects (some of the identified variants were associated with mRNA transcription in human liver or lymphoblastoid cells), dysfunction of the encoded proteins (caused by missense variations at the functional domains), or other unknown pathways. These findings may help in the interpretation of liver-enzyme tests and provide candidate genes for liver diseases of viral, metabolic, autoimmune, or toxic origin. The specific associations with ALP levels may point to genes for bone or intestinal diseases.
Yuan
Xin
X
Genetics Division, GlaxoSmithKline, King of Prussia, PA 19406, USA.
Waterworth
Dawn
D
Perry
John R B
JR
Lim
Noha
N
Song
Kijoung
K
Chambers
John C
JC
Zhang
Weihua
W
Vollenweider
Peter
P
Stirnadel
Heide
H
Johnson
Toby
T
Bergmann
Sven
S
Beckmann
Noam D
ND
Li
Yun
Y
Ferrucci
Luigi
L
Melzer
David
D
Hernandez
Dena
D
Singleton
Andrew
A
Scott
James
J
Elliott
Paul
P
Waeber
Gerard
G
Cardon
Lon
L
Frayling
Timothy M
TM
Kooner
Jaspal S
JS
Mooser
Vincent
V
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D015331:Cohort Studies; D004798:Enzymes / Q000097:blood*; D005260:Female; D005828:Genetics, Population; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D005723:gamma-Glutamyltransferase / Q000097:blood
D004798:Enzymes; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase